1. Field of the Disclosure
This disclosure is generally directed to dry blend, powder formulations and dosage forms of tetrahydrobiopterin. In particular, provided is a dry blending process for tetrahydrobiopterin (i.e., BH4 dihydrochloride), the powder of which can be stably packaged in sachets, stable capsule dosage forms containing a pullulan-free capsule shell, or dissolved into a stable solution and stored in hermetically and non-hermetically sealed containers.
2. Background
Tetrahydrobiopterin (also referred to as BH4 or sapropterin) is a biogenic amine of the naturally occurring pterin family and is a cofactor for a number of different enzymes, including phenylalanine hydroxylase (PAH), tyrosine 3-hydroxylase, tryptophan 5-hydroxylase, and nitric oxide synthase (NOS). Accordingly, BH4 is involved in the synthesis of the amino acids phenylalanine, tyrosine and tryptophan, and the neurotransmitters dopamine and serotonin. Moreover, BH4 is essential for NOS-catalyzed oxidation of L-arginine to L-citrulline and nitric oxide. Pterins are present in physiological fluids and tissues in reduced and oxidized forms, but only the 5,6,7,8-tetrahydrobiopterin is biologically active. More specifically, it is the 6R enantiomer of BH4 that is known to be the biologically active enantiomer. For a detailed review of the synthesis of and disorders associated with BH4, see Blau et al., “Disorders of tetrahydrobiopterin and related biogenic amines” in C. R. Scriver et al., eds., The Metabolic and Molecular Bases of Inherited Disease, 8th ed., pp. 1275-1776, McGraw-Hill (New York, 2001).
Tetrahydrobiopterin is unstable, readily undergoes aerobic oxidation at room temperature, and has a shelf-life of less than 8 hours at room temperature in aqueous solutions. Due to the instability of BH4, most tetrahydrobiopterin products available on the market need to be specially packaged or kept frozen. The instability of such BH4 compositions is undesirable, and significant degradation resulting from improper storage could hinder therapy of patients. One example of a stable BH4 tablet composition is disclosed in WO 2006/055511, which is incorporated herein by reference in its entirety. Such a tablet composition is sold under the tradename KUVAN®. There is a need for additional formulations of BH4 suitable for pharmaceutical use.